| Summary: | Non-alcoholic fatty liver disease (NAFLD) is a rising epidemic affecting around 25% of the global population, in parallel with increasing worldwide rates of obesity and metabolic syndrome. NAFLD is a complex condition with a genetic component shared with other liver or related metabolic disorders. To date, healthy lifestyle modifications based on diet and physical activity are a cornerstone of the NAFLD therapy, where the genetic involvement appears to affect treatment outcomes by interacting with environmental factors. In this context, this research focused on the following objectives: 1) To analyze the association of the SH2B1 rs7359397 gene polymorphism with steatosis severity in subjects with obesity and NAFLD (Chapter 1); 2) To evaluate the influence of the SH2B1 rs7359397 genetic variant on changes in body composition, metabolic status and liver health after 6-month energy-restricted treatment in overweight/obese subjects with NAFLD (Chapter 2); 3) To assess three different genetic risk scores (GRSs) based on Fatty Liver Index (FLI), Magnetic Resonance Imaging (MRI) and lipidomic (OWLiver®-test) for a nutrigenetic personalized management of NAFLD after a 6-months weight-loss nutritional treatment (Chapter 3); and 4) To build a predictive model based on genetic and hepatic health information, deeming insulin resistance markers in order to personalize dietary treatment in overweight/obese subjects with NAFLD (Chapter 4). Regarding the first objective, the results suggested that the risk genotype concerning the SH2B1 rs7359397 genetic variant was associated with higher homeostatic model assessment of insulin resistance, FLI and protein intake. while lower mono- unsaturated fatty acid and fiber intake was found. Moreover, individuals with the minor risk allele also showed a higher susceptibility of advanced stages of NAFLD. Considering the second objective, carriers of the minor allele of the SH2B1 rs7359397 genetic variant showed a better response to a weight-loss dietary intervention in terms of hepatic health and liver status. Furthermore, adherence to Mediterranean dietary pattern rich in fiber and other components such as omega-3 fatty acids might boost these benefits. In relation to the third objective, three GRSs based on different diagnostic tools for detecting NAFLD were able to predict the improvement in liver health after a 6-month energy-restricted nutritional treatment. These associations were particularly influenced by factors such as insulin resistance, inflammatory biomarkers and specific nutrients. Concerning the fourth objective, the designed GRS was able to predict the change in FLI adjusted by diet, age and sex, allowing to personalize the most suitable diet for 72% of the volunteers. Similar models were also able to predict the changes on variables related to insulin resistance depending on diet. In conclusion, new diagnostics and personalized intervention approaches based on nutrigenetics instruments could help to improve precision nutrition management in subjects with NAFLD, reducing the severity, some associated comorbidities and impact on healthcare concerning this disease, as well as explaining the benefits of individualized prescribed dietary patterns.
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